ACP 2012 - Oral Pharmacologic Treatment of Type 2 DM

Clinical Guideline
Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline From the American College of Physicians
Amir Qaseem, MD, PhD, MHA; Linda L. Humphrey, MD, MPH; Donna E. Sweet, MD; Melissa Starkey, PhD; and Paul Shekelle, MD, PhD, for the Clinical Guidelines Committee of the American College of Physicians*
Description: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the comparative effectiveness and safety of type 2 diabetes medications. Methods: This guideline is based on a systematic evidence review evaluating literature published on this topic from 1966 through April 2010 that was identified by using MEDLINE (updated through December 2010), EMBASE, and the Cochrane Central Register of Controlled Trials. Searches were limited to English-language publications. The clinical outcomes evaluated for this guideline included all-cause mortality, cardiovascular morbidity and mortality, cerebrovascular morbidity, neuropathy, nephropathy, and retinopathy. This guideline grades the evidence and recommendations by using the American College of Physicians clinical practice guidelines grading system. Recommendation 1: ACP recommends that clinicians add oral pharmacologic therapy in patients diagnosed with type 2 diabetes
when lifestyle modifications, including diet, exercise, and weight loss, have failed to adequately improve hyperglycemia (Grade: strong recommendation; high-quality evidence). Recommendation 2: ACP recommends that clinicians prescribe monotherapy with metformin for initial pharmacologic therapy to treat most patients with type 2 diabetes (Grade: strong recommendation; high-quality evidence). Recommendation 3: ACP recommends that clinicians add a second agent to metformin to treat patients with persistent hyperglycemia when lifestyle modifications and monotherapy with metformin fail to control hyperglycemia (Grade: strong recommendation; highquality evidence).
Ann Intern Med. 2012;156:218-231. For author affiliations, see end of text.
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iabetes mellitus is the seventh leading cause of death in the United States. In addition, it is a leading cause of morbidity and leads to microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (coronary artery, cerebrovascular, and peripheral vascular disease) complications. Type 2 diabetes mellitus is the most common form of the disease (affecting 90% to 95% of persons with diabetes), with a prevalence of approximately 25.8 million people in the United States (1). Type 2 diabetes increases with age, and nearly 27% of people in the United States older than 65 years have diabetes (1). In addition, because of increasing rates of obesity in the United States, the incidence and prevalence of diabetes mellitus are increasing substantially (1). The costs associated
See also: Print Summary for Patients. . . . . . . . . . . . . . . . . . . . . . . I-36 Web-Only Appendix Tables Conversion of graphics into slides
with diabetes in the United States alone reached $174 billion in 2007 (2). Good management of type 2 diabetes with pharmacologic and nonpharmacologic therapies is important and includes patient education, evaluation for microvascular and macrovascular complications, treatment of glycemia, and minimization of cardiovascular and other long-term risks. In the United States, 11 unique classes of drugs are approved by the U.S. Food and Drug Administration (FDA) for the treatment of hyperglycemia in type 2 diabetes; all of these medications vary in cost and risk (3). Among people diagnosed with diabetes, most will receive more than 1 class of diabetes medication: 14% take both insulin and oral medication and 58% take oral medications only (2). The purpose of this American College of Physicians (ACP) guideline is to address the pharmacologic management of type 2 diabetes by comparing the effectiveness and safety of currently available oral pharmacologic treatment for type 2 diabetes. The target audience for this guideline includes all clinicians, and the target patient population comprises all adults with type 2 diabetes. These recommendations are based on a systematic evidence review by Bennett and colleagues (4) and an evidence report spon-
* This paper, written by Amir Qaseem, MD, PhD, MHA; Linda L. Humphrey, MD, MPH; Donna E. Sweet, MD; Melissa Starkey, PhD; and Paul Shekelle, MD, PhD, was developed for the Clinical Guidelines Committee of the American College of Physicians: Paul Shekelle, MD, PhD (Chair); Roger Chou, MD; Paul Dallas, MD; Thomas D. Denberg, MD, PhD; Nick Fitterman, MD; Mary Ann Forciea, MD; Robert H. Hopkins Jr., MD; Linda L. Humphrey, MD, MPH; Tanveer P. Mir, MD; Holger J. Schu nemann, MD, PhD; Donna E. Sweet, MD; and David S. Weinberg, MD, MSc. Approved by the ACP Board of Regents on 19 November 2011. 218 2012 American College of Physicians
This on article has been corrected. The specific correction appears on the last page of this document. Downloaded From: http://annals.org/ 12/22/2013 The original version (PDF) is available at www.annals.org.
Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus
Clinical Guideline
sored by the Agency for Healthcare Research and Quality (AHRQ) (5). The 2011 review expands on a 2007 AHRQ evidence report (6), which discussed mortality, microvascular and macrovascular outcomes, intermediate outcomes, and adverse effects for drugs available until 2006. The 2011 report focuses on head-to-head comparisons and includes direct comparisons for monotherapy and dualtherapy regimens. Combination therapies with more than 2 agents were not included in the review. The 2011 report also includes evidence for more recently approved diabetes medications and excludes data on -glucosidase inhibitors, such as acarbose (5).
Table 1. The American College of Physicians Guideline

Grading System*
Quality of Evidence Strength of Recommendation Benefits Clearly Outweigh Risks and Burden or Risks and Burden Clearly Outweigh Benefits High Moderate Low Strong Strong Strong Benefits Finely Balanced With Risks and Burden
Weak Weak Weak
Insufficient evidence to determine net benefits or risks
METHODS
The evidence report informing this guideline reviewed data for 11 FDA-approved, unique classes of drugs for the treatment of hyperglycemia in type 2 diabetes (Appendix Table 1, available at www.annals.org). This guideline is based on a systematic evidence review that addressed the following key questions: Key question 1: In adults aged 18 years or older with type 2 diabetes mellitus, what is the comparative effectiveness of these treatment options for the intermediate outcomes of glycemic control (in terms of hemoglobin A1c [HbA1c]), weight, or lipids? Key question 2: In adults aged 18 years or older with type 2 diabetes mellitus, what is the comparative effectiveness of these treatment options in terms of the following long-term clinical outcomes: all-cause mortality, cardiovascular mortality, cardiovascular and cerebrovascular morbidity (for example, myocardial infarction and stroke), retinopathy, nephropathy, and neuropathy? Key question 3: In adults aged 18 years or older with type 2 diabetes mellitus, what is the comparative safety of these treatment options in terms of the following adverse events and side effects: hypoglycemia, liver injury, congestive heart failure, severe lactic acidosis, cancer, severe allergic reactions, hip and nonhip fractures, pancreatitis, cholecystitis, macular edema or decreased vision, and gastrointestinal side effects? Key question 4: Do safety and effectiveness of these treatment options differ across subgroups of adults with type 2 diabetes, in particular for adults aged 65 years or older, in terms of mortality, hypoglycemia, and cardiovascular and cerebrovascular outcomes? The systematic evidence review was conducted by the Johns Hopkins Evidence-based Practice Center. This review updates a 2007 systematic review on the same topic and focuses on head-to-head comparisons rather than placebo-controlled trials (6, 7). The literature search included studies identied by using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. The studies that were selected included observational studies and trials published in the English language from 1966 through April 2010. In addition, the MEDLINE search
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* Adopted from the classication developed by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) workgroup.
was updated to December 2010 for long-term clinical outcomes (all-cause mortality, cardiovascular morbidity and mortality, nephropathy, neuropathy, and retinopathy). Reference lists, FDA medical reviews, European Public Assessment Reports, Health Canada Product Monographs, unpublished data from pharmaceutical companies, and public registries of clinical trials were also reviewed. Standardized forms were used for data abstraction, and each article underwent double review. Quality of randomized, controlled trials (RCTs) was assessed by using the Jadad criteria, and quality of observational studies was assessed as recommended in the Guide for Conducting Comparative Effectiveness Reviews (8, 9). The I2 statistic was used to determine study heterogeneity (10). Further details about the methods and inclusion and exclusion criteria applied in the evidence review are available in the full AHRQ report (5). This guideline rates the recommendations by using the American College of Physicians guideline grading system, which is based on the GRADE system (Table 1). Details of the ACP guideline development process can be found in ACPs methods paper (11). This guideline focuses on results that were statistically signicant, and details on non statistically signicant results are available in the full AHRQ report (5).
COMPARATIVE EFFECTIVENESS OF TYPE 2 DIABETES MEDICATIONS ON INTERMEDIATE OUTCOMES

Table 2 summarizes the key ndings and strength of evidence for intermediate outcomes comparing various diabetes medications as monotherapy or as combination therapy.
HbA1c Levels
Evidence was gathered from 104 head-to-head RCTs that varied from low to high quality and offered direct evidence from comparisons among various type 2 diabetes medications (5).
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Clinical Guideline
Table 2. Key Findings and Strength of Evidence for Intermediate Outcomes*

Comparison Monotherapy vs. monotherapy Metformin vs. TZD HbA1c Weight/BMI LDL Cholesterol HDL Cholesterol Triglycerides
Neither favored, moderate
Favors metformin, high
Favors metformin, moderate Favors metformin, high Favors metformin, high Favors metformin, moderate Unclear, low
Neither favored, moderate Favors pioglitazone, high
Sulfonylurea DPP-4 inhibitor Meglitinide
GLP-1 agonist TZD vs. TZD Sulfonylurea
Neither favored, high Favors metformin, moderate Neither favored, low Favors metformin, low Insufficient Neither favored, moderate Neither favored, moderate Insufficient Unclear, low Neither favored, low Insufficient Neither favored, low Neither favored, high Neither favored, low Unclear, low
Favors metformin, high Favors metformin, moderate Unclear, low
Neither favored, high Neither favored, low Unclear, low
Favors metformin, moderate Favors pioglitazone, high Favors metformin, moderate Neither favored, low Unclear, low
Insufficient Neither favored, low Favors sulfonylurea, low Insufficient Unclear, low
Insufficient Favors pioglitazone, low Favors sulfonylurea, low
Insufficient Favors pioglitazone, moderate Favors rosiglitazone, low Favors pioglitazone, moderate Insufficient Unclear, low Favors pioglitazone, low Insufficient Neither favored, low Neither favored, high
Insufficient Neither favored, low Unclear, low Favors pioglitazone, low Insufficient Unclear, low Favors pioglitazone, low Insufficient Neither favored, low Neither favored, moderate
DPP-4 inhibitor Meglitinide
Insufficient Unclear, low
GLP-1 agonist Sulfonylurea vs. DPP-4 inhibitor Meglitinide
Insufficient Unclear, low Neither favored, high
Insufficient Neither favored, low Neither favored, low
GLP-1 agonist DPP-4 inhibitor vs. Meglitinide GLP-1 agonist
Favors GLP-1 agonist, moderate Insufficient Insufficient
Unclear, low
Insufficient
Unclear, low
Insufficient Insufficient
Unclear, low Insufficient
Monotherapy vs. combination therapy Metformin vs. Metformin TZD Favors metformin TZD, high
Favors metformin, high Unclear, low
Metformin sulfonylurea Metformin DPP-4 inhibitor Metformin meglitinide
Favors metformin sulfonylurea, high Favors metformin DPP-4 inhibitor, moderate Favors metformin meglitinides, low
Favors metformin, high Neither favored, moderate Favors metformin, low
Neither favored, low Neither favored, low
Favors metformin rosiglitazone, high Favors metformin pioglitazone, low Neither favored, low Neither favored, moderate
Favors metformin, high Unclear, low Neither favored, low Favors metformin DPP-4 inhibitor, low Favors metformin meglitinides, low
Unclear, low
Neither favored, low
Combination therapy vs. combination therapy Metformin TZD vs. Metformin sulfonylurea Neither favored, moderate
Favors metformin sulfonylurea, moderate
Favors metformin sulfonylurea, moderate Favors metformin sulfonylurea, low Favors metformin meglitinides, low Insufficient Insufficient
Favors metformin rosiglitazone, moderate Favors metformin pioglitazone, low Favors metformin rosiglitazone, low Insufficient Unclear, low Insufficient
Metformin meglitinide Metformin DPP-4 inhibitor
Neither favored, low Insufficient Neither favored, low
Unclear, low
Favors metformin DPP-4 inhibitor, low
Neither favored, moderate Favors metformin pioglitazone, moderate Neither favored, low Insufficient Favors metformin sitagliptin, low Insufficient
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Clinical Guideline
Table 2Continued
Comparison Metformin GLP-1 agonist HbA1c Neither favored, low Weight/BMI Favors metformin GLP-1 agonist, low Insufficient LDL Cholesterol Unclear, low HDL Cholesterol Favors metformin rosiglitazone, low Insufficient Insufficient Favors metformin pioglitazone, low Triglycerides Favors metformin GLP-1 agonist, low Insufficient Insufficient* Favors metformin pioglitazone, low Unclear, low Insufficient
TZD sulfonylurea
Favors TZD sulfonylurea, low
Insufficient Neither favored, low
Metformin sulfonylurea vs. Metformin meglitinide Metformin DPP-4 inhibitor Metformin GLP-1 agonist TZD sulfonylurea
Insufficient Unclear, low Neither favored, low
Unclear, low Favors metformin DPP-4 inhibitor, low Favors metformin GLP-1 agonist, low Favors metformin sulfonylurea, moderate Favors metformin basal insulin, low Neither favored, low Favors metformin GLP-1 agonist, low
Unclear, low Insufficient
Neither favored, low Insufficient
Unclear, low
Insufficient
Insufficient
Insufficient
Favors metformin sulfonylurea, low
Unclear, low Favors metformin sulfonylurea, low Insufficient
Unclear, low Favors pioglitazone sulfonylurea, low Insufficient
Metformin premixed insulin Metformin basal insulin vs. Metformin premixed insulin Metformin GLP-1 agonist Metformin DPP-4 inhibitor vs. Metformin GLP-1 agonist
Unclear, low
Unclear, low Favors pioglitazone sulfonylurea, low Insufficient
Neither favored, low Neither favored, low
Favors metformin GLP-1 agonist, low
Favors metformin GLP-1 agonist, low
Unclear, low
Neither favored, low
Unclear, low
BMI body mass index; DPP-4 dipeptidyl peptidase-4; GLP-1 glucagon-like peptide-1; HbA1c hemoglobin A1c; HDL high-density lipoprotein; LDL low-density lipoprotein; TZD thiazolidinedione. * Unless otherwise noted, comparisons and intermediate outcomes were graded as insufcient because there were no studies. For comparisons with rosiglitazone. For comparisons with pioglitazone. For comparisons with repaglinide. For comparisons with nateglinide.
Monotherapy vs. Monotherapy
Most diabetes medications had similar efcacy and reduced HbA1c levels by an average of 1 percentage point (4). However, pooled results from 3 studies (reported in 4 papers) showed that metformin decreased HbA1c levels more than did dipeptidyl peptidase-4 (DPP-4) inhibitors (mean difference, 0.37 percentage point [95% CI, 0.54 to 0.20 percentage point]; I2 0%; moderatequality evidence) (1215).
Monotherapy vs. Combination Therapy
DPP-4 inhibitor (mean difference, 0.69 percentage point [CI, 0.56 to 0.82 percentage point]; I2 97%; moderatequality evidence), metformin plus a thiazolidinedione (mean difference, 0.66 percentage point [CI, 0.45 to 0.86 percentage point]; I2 84%; high-quality evidence). Comparisons between different combinations of drugs showed similar effects, although few trials were available. Evidence from trials that included glucagon-like peptide-1 (GLP-1) agonists was graded as insufcient or low.
All dual-regimen combination therapies were more efcacious than monotherapy and reduced HbA1c levels by an average of 1 additional percentage point compared with monotherapy (4). Pooled data for the combination of metformin with another agent compared with metformin monotherapy showed a greater decrease in HbA1c levels: metformin plus a sulfonylurea (mean difference, 1.00 percentage point [CI, 0.75 to 1.25 percentage point]; I2 85%; high-quality evidence), metformin plus a
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Combination Therapy vs. Combination Therapy
One RCT showed that the combination of metformin plus a GLP-1 agonist (liraglutide) statistically signicantly decreased HbA1c levels by 0.34 to 0.60 percentage points in low- and high-dose combinations compared with metformin plus a DPP-4 inhibitor (sitagliptin) (low-quality evidence) (16). A post hoc analysis of a small RCT showed that the combination of a thiazolidinedione plus a sulfonylurea decreased HbA1c levels by 0.03 percentage point
Clinical Guideline
(P 0.04) more than did the combination of metformin plus a thiazolidinedione (low-quality evidence) (17). All other combinations had similar efcacy in reducing HbA1c levels (5).
Body Weight
(low-quality evidence) (58). Combination of metformin plus a GLP-1 agonist also resulted in greater weight loss compared with the combination of metformin plus a sulfonylurea, as shown in 2 RCTs (low-quality evidence) (49, 59).
Plasma Lipid Levels
Evidence was gathered from 79 head-to-head RCTs that varied from low to high quality and offered direct evidence from comparisons among various type 2 diabetes medications (5).
Pooled results showed that monotherapy with metformin resulted in more weight loss compared with thiazolidinediones (mean difference, 2.6 kg [CI, 4.1 to 1.2 kg]; I2 85%; high-quality evidence) (18 25), sulfonylureas (mean difference, 2.7 kg [CI, 3.5 to 1.9 kg]; I2 51%; high-quality evidence) (23, 26 36), and DPP-4 inhibitors (mean difference, 1.4 kg [CI, 1.8 to 1.0; I2 5%; moderate-quality evidence) (12, 14, 15). Monotherapy with a thiazolidinedione compared with a sulfonylurea resulted in more weight loss (mean difference, 1.2 kg [CI, 0.6 to 1.9 kg]; I2 0%; low-quality evidence) (23, 37 40). Compared with GLP-1 agonists, sulfonylureas showed more weight gain (mean difference, 2.5 kg [CI, 1.2 to 3.8 kg]; I2 93%; moderate-quality evidence), although the studies were very heterogeneous (41 43).
Evidence was gathered from 74 head-to-head RCTs that varied from low to high quality and offered direct evidence from comparisons among various type 2 diabetes medications. Most diabetes medications had a small to moderate effect on lipid levels: 5 to 10 mg/dL for lowdensity lipoprotein (LDL) cholesterol, 3 to 5 mg/dL for high-density lipoprotein (HDL) cholesterol, and 10 to 30 mg/dL for triglycerides (5).
LDL Cholesterol Levels
Pooled data showed that metformin monotherapy was more effective in decreasing body weight than metformin plus a thiazolidinedione (mean difference, 2.2 kg [CI, 2.6 to 1.9 kg]; I2 0%; high-quality evidence) (24, 44 47) or metformin plus a sulfonylurea (mean difference, 2.3 kg [CI, 3.3 to 1.2 kg]; I2 83%; highquality evidence) (29 36, 48, 49). Metformin was also favored when compared with metformin plus meglitinides in 2 RCTs (50, 51).
Pooled data showed that the combination of metformin plus a sulfonylurea was favored for weight compared with metformin plus a thiazolidinedione (mean difference, 0.9 kg [CI, 0.4 to 1.3 kg]; I2 0%; moderatequality evidence) (5256). Pooled data also showed that the combination of metformin plus a sulfonylurea is favored over the combination of a thiazolidinedione and sulfonylurea (mean difference, 3.17 [CI, 5.21 to 1.13 kg]; I2 83%; moderate-quality evidence). Compared with the combination of metformin plus a sulfonylurea (glipizide), metformin plus a DPP-4 inhibitor (sitagliptin) statistically signicantly reduced weight in 1 RCT (mean difference, 2.5 kg [CI, 3.1 to 2.0 kg]) (57), and the trend continued when the study was extended for another year (mean difference, 2.3 kg [CI, 3.0 to 1.6 kg])
Monotherapy vs. Monotherapy. Monotherapy with metformin decreased LDL more than did thiazolidinedione monotherapy with pioglitazone (mean difference, 14.21 mg/dL [CI, 15.29 to 13.13 mg/dL]; I2 0%; highquality evidence) (18, 22, 25, 60 62) or rosiglitazone (mean difference, 12.76 mg/dL [CI, 23.96 to 1.56 mg/dL]; I2 56%; moderate-quality evidence) (20, 21, 24, 63 65). Metformin was also favored over both sulfonylureas (mean difference, 10.1 mg/dL [CI, 13.3 to 7.0 mg/dL]; I2 85%; high-quality evidence) (28, 30, 31, 33, 35, 36, 66, 67) and DPP-4 inhibitors (mean difference, 5.9 mg/dL [CI, 9.7 to 2.0 mg/dL]; I2 28%; moderate-quality evidence) (12, 14, 15). Pooled data showed that monotherapy with sulfonylureas more effectively reduced LDL cholesterol than did pioglitazone (mean difference, 7.12 mg/dL [CI, 5.26 to 8.98 mg/dL]; I2 4%; low-quality evidence) (40, 68, 69), and 2 RCTs showed that rosiglitazone increased LDL cholesterol compared with sulfonylurea monotherapy (low-quality evidence) (37, 39). Monotherapy vs. Combination Therapy. Compared with metformin monotherapy, combination of metformin with other agents did not show any benet (5). Combination Therapy vs. Combination Therapy. The combination of metformin plus a sulfonylurea was favored over metformin plus a thiazolidinedione, as pooled data showed for rosiglitazone (mean difference, 13.5 mg/dL [CI, 9.1 to 17.9 mg/dL]; I2 0%; moderate-quality evidence) (54, 55, 70, 71) and a single RCT showed for pioglitazone (mean difference, 8.5 mg/dL; P 0.03; lowquality evidence) (56). The combination of metformin plus a sulfonylurea was also favored over the combination of pioglitazone plus a sulfonylurea, as reported in 2 RCTs (low-quality evidence) (72, 73).
HDL Cholesterol Levels
Monotherapy vs. Monotherapy. Monotherapy with metformin was less effective than a thiazolidinedione (pioglitazone) at increasing HDL cholesterol levels (mean differwww.annals.org
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ence, 3.2 mg/dL [CI, 4.3 to 2.1 mg/dL]; I2 93%; high-quality evidence) (18, 22, 23, 25, 60 62, 74). Monotherapy with a thiazolidinedione more effectively increased HDL cholesterol levels compared with a sulfonylurea, as shown by pooled data for pioglitazone (mean difference, 4.27 mg/dL [CI, 1.93 to 6.61 mg/dL]; I2 99%; moderate-quality evidence) (23, 40, 59, 68, 74, 75) and data from 2 RCTs for rosiglitazone (range in median between-group difference, 3.5 to 7.7 mg/dL; low-quality evidence) (37, 39). Two RCTs also showed that monotherapy with pioglitazone was favored over meglitinides (mean difference, 7 mg/dL; low-quality evidence) (75, 76). When thiazolidinediones were compared, pioglitazone increased HDL cholesterol levels more than did rosiglitazone (mean difference, 2.33 mg/dL [CI, 3.46 to 1.20 mg/ dL]; I2 0%; moderate-quality evidence) (7779). Monotherapy vs. Combination Therapy. The combination of metformin with a thiazolidinedione was better than monotherapy with metformin, as shown by pooled data for rosiglitazone (mean difference, 2.8 mg/dL [CI, 3.5 to 2.2 mg/dL]; I2 83%; high-quality evidence) (24, 44, 45, 47, 80 82), and 2 RCTs favored the combination of metformin plus pioglitazone over metformin monotherapy (46, 83). Combination Therapy vs. Combination Therapy. The combination of metformin plus a thiazolidinedione was favored over the combination of metformin and a sulfonylurea, as shown by pooled data for rosiglitazone (mean difference, 2.7 mg/dL [CI, 1.4 to 4.1 mg/dL]; I2 0%; moderate-quality evidence) (54, 55, 70, 71), data from 2 RCTs for pioglitazone (between-group differences ranged from 5.1 mg/dL [P 0.001] to 5.8 mg/dL [P 0.001]; low-quality evidence) (56, 84). Post hoc analysis in 1 RCT showed that the combination of metformin plus pioglitazone increased HDL cholesterol levels (2.3 mg/dL; P 0.009) compared with pioglitazone plus sulfonylurea (0.4 mg/dL; P 0.62) (low-quality evidence) (84). Three RCTs found an increase in HDL cholesterol levels with the combination of pioglitazone plus a sulfonylurea compared with metformin plus a sulfonylurea (low-quality evidence) (72, 73, 84).
Triglyceride Levels
mg/dL [CI, 49.15 to 14.10 mg/dL]; I2 91%; lowquality evidence) (23, 40, 68, 69, 74, 75). Two RCTs also favor pioglitazone over meglitinides for reducing triglyceride levels (75, 76). Monotherapy vs. Combination Therapy. Metformin monotherapy decreased triglyceride levels more than metformin plus a thiazolidinedione (rosiglitazone) (mean difference, 14.5 mg/dL [CI, 15.8 to 13.3 mg/dL]; I2 0%; high-quality evidence) (24, 44, 45, 47, 80 82). However, than with metformin monotherapy, combination therapy consisting of metformin plus a DPP-4 inhibitor (mean difference, 20.68 mg/dL [CI, 0.79 to 42.14 mg/dL]; low-quality evidence; P 0.05) (14, 15, 47, 85) or metformin plus meglitinides (data from a single RCT: range of between-group differences, 17.8 to 8.9 mg/dL; P 0.05 for the higher-dose nateglinide; low-quality evidence) (50) decreased triglyceride levels more than did metformin alone. Combination Therapy vs. Combination Therapy. Two RCTs showed that the combination of metformin plus pioglitazone decreased triglyceride levels more than did metformin plus a sulfonylurea (between-group differences ranged from 10 mg/dL [P 0.30] to 24.9 mg/dL [P 0.045]; moderate-quality evidence) (56, 84). One small RCT found that metformin plus a GLP-1 agonist fared better than the combination of metformin plus rosiglitazone (between-group mean difference in triglyceride levels, 36.3 mg/dL; signicance not reported; lowquality evidence) (86). In addition, data from 4 RCTs showed that the combination of a thiazolidinedione (pioglitazone) plus a sulfonylurea decreased triglyceride levels more or increased triglyceride levels less than the combination of metformin plus a sulfonylurea (low-quality evidence) (72, 73, 84, 87).
COMPARATIVE EFFECTIVENESS OF TYPE 2 DIABETES MEDICATIONS ON LONG-TERM CLINICAL OUTCOMES

A total of 66 studies (46 RCTs; duration, 12 weeks to 6 years) reported comparative effectiveness of oral diabetes medications on long-term outcomes. The mean age of participants ranged from 48 years to 75 years (5). It was difcult to draw conclusions about the comparative effectiveness of type 2 diabetes medications on all-cause mortality, cardiovascular morbidity and mortality, and microvascular outcomes because of low quality or insufcient evidence (4). Appendix Table 2 (available at www.annals.org) summarizes the ndings and strength of evidence for long-term outcomes comparing various diabetes medications as monotherapy or combination therapy.
Mortality (All-Cause and Cardiovascular)
Monotherapy vs. Monotherapy. Metformin monotherapy decreased triglyceride levels compared with sulfonylureas (mean difference, 8.6 mg/dL [CI, 15.6 to 1.6 mg/dL]; I2 92%; moderate-quality evidence) (23, 26, 28 31, 33, 35, 36, 66, 74) and rosiglitazone (mean difference, 26.86 mg/dL [CI, 49.26 to 4.47 mg/dL]; I2 70%; moderate-quality evidence) (20, 21, 24, 63 65). However, pooled data from other studies showed that pioglitazone decreased triglyceride levels more than did metformin (mean difference, 27.2 mg/dL [CI, 24.4 to 30.0 mg/dL]; I2 0%; high-quality evidence) (18, 22, 23, 25, 60 62, 74) and sulfonylureas (mean difference, 31.62
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Five RCTs (30, 31, 33, 88, 89) and 11 observational studies (90 100) were examined for all-cause mortality between metformin monotherapy and sulfonylurea monotherapy. These studies indicate that metformin was associated with lower all-cause mortality compared with
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sulfonylureas (low-quality evidence). Metformin was also favored over sulfonylureas for cardiovascular mortality (low-quality evidence), as evidenced by 4 cohort studies (92, 94, 96, 101), although 1 prospective cohort study (94) showed a slightly higher cardiovascular mortality rate for metformin than for sulfonylurea monotherapy. Also, ADOPT (A Diabetes Outcome Progression Trial) (89) reported only 1 fatal CHF event in patients treated with either metformin or glyburide (nonstatistically signicant difference), but patients treated with glyburide generally experienced fewer CHF as well as cardiovascular events.
Morbidity (Cardiovascular and Cerebrovascular)
compared with no patients treated with a DPP-4 inhibitor; moderate-quality evidence) (114) and GLP-1 agonists (data from 3 RCTs; high-quality evidence) (41 43). Monotherapy with meglitinides resulted in more hypoglycemia compared with metformin (OR, 3.00 [CI, 1.80 to 5.20]; I2 0%; moderate-quality evidence) (51, 115118) or thiazolidinediones (2 RCTs: relative risk [RR], 1.2 [CI, 0.8 to 1.8] [76]; RR, 1.6 [CI, 1.0 to 2.6] [119]; lowquality evidence).
Monotherapy with metformin was linked to lower cardiovascular morbidity than combination therapy for metformin plus sulfonylureas (low-quality evidence), as shown by 1 RCT (5% vs. 14% adverse cardiovascular events) (35) and 1 cohort study (adjusted incidence of hospitalization for myocardial infarction or coronary revascularization, 13.90 vs. 19.44 per 1000 person-years) (102). Evidence for all other comparisons was insufcient or unclear (Appendix Table 2) (5).
Retinopathy, Nephropathy, and Neuropathy
Compared with metformin monotherapy, the combination of metformin plus a thiazolidinedione (OR, 1.57 [CI, 1.01 to 2.43]; I2 0%; moderate-quality evidence) (24, 44 47, 81 83), metformin plus a sulfonylurea (RR, 1.6 to 25 in 9 RCTs; moderate-quality evidence) (27, 29 31, 35, 36, 48, 49, 88), and metformin plus meglitinides (OR, 2.75 [CI, 0.98 to 7.71]; I2 21%; low-quality evidence; P 0.05) (49 51) resulted in an increase in hypoglycemia.
There was moderate-quality evidence for nephropathy only for the comparison between pioglitazone and metformin. In the 2 studies that addressed this comparison, pioglitazone signicantly reduced the urinary albumin creatinine ratio by 19% (25) and 15% (72), whereas the ratio was unchanged in patients treated with metformin.
COMPARATIVE SAFETY MEDICATIONS
OF
TYPE 2 DIABETES
Appendix Table 3 (available at www.annals.org) summarizes the ndings and strength of evidence for adverse effects among various diabetes medications as monotherapy or combination therapy.
Hypoglycemia
The combination of metformin plus a sulfonylurea increased the risk for hypoglycemia by about 6 times compared with the combination of metformin plus a thiazolidinedione (OR, 5.80 [CI, 4.30 to 7.70]; I2 0%; highquality evidence) (17, 52, 54, 56, 71). One large RCT reported that metformin plus a thiazolidinedione resulted in fewer hypoglycemic events compared with a thiazolidinedione plus a sulfonylurea (0.05 vs. 0.47 event per 100 person-years of follow-up; low-quality evidence) (120). Another study found more hypoglycemic symptoms in patients treated with the combination of metformin plus a sulfonylurea than with the combination of a thiazolidinedione plus a sulfonylurea (RR, 1.3 [CI, 0.9 to 2]; low-quality evidence) (121).
Other Adverse Effects
No particular monotherapy or combination therapy increased severe hypoglycemia (generally dened as hypoglycemia requiring assistance for resolution) compared with the other treatments (4).
Pooled results from monotherapy trials show that sulfonylureas increase the risk for mild to moderate hypoglycemia compared with metformin (odds ratio [OR], 4.60 [CI, 3.20 to 6.50]; I2 68%; high-quality evidence) (27, 29 32, 36, 66, 74, 88), thiazolidinediones (OR, 3.88 [CI, 3.05 to 4.94]; I2 41%; high-quality evidence) (37 40, 74, 89, 103105), and meglitinides (OR, 0.78 [CI, 0.55 to 1.12]; I2 18%; low-quality evidence) (106 113). Data from RCTs also indicate that other agents were favored over sulfonylureas for hypoglycemia: DPP-4 inhibitors (data from 1 RCT showed that 21 of 123 patients treated with a sulfonylurea had mild or moderate hypoglycemia
Evidence was insufcient to show any difference among the various type 2 diabetes medications on liver injury. Evidence from 51 studies was evaluated to determine gastrointestinal effects (5). Evidence examined from studies addressing these effects that compared metformin monotherapy with thiazolidinediones (high-quality evidence) (22, 24, 25, 89, 122), sulfonylureas (moderate-quality evidence) (26, 27, 29 33, 35, 66, 88, 89), DPP-4 inhibitors (moderate-quality evidence) (12, 14, 15), or meglitinides (low-quality evidence) (115118) report more gastrointestinal adverse effects with metformin. Trials comparing metformin monotherapy with combination metformin plus thiazolidinedione therapy (moderate-quality evidence) (24, 44 47, 80 82) or metformin plus sulfonylurea therapy (moderate-quality evidence) (27, 29 33, 35, 49, 66, 88, 123) generally favored the combination therapy, although the metformin dosage was typically lower in the
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Clinical Guideline
combination group, possibly accounting for this difference. One RCT reported more dyspepsia with a combination of metformin plus a meglitinide than with metformin plus a sulfonylurea (13% vs. 3%; low-quality evidence) (124). Two RCTs reported more diarrhea in combination treatment with metformin plus a sulfonylurea than with a thiazolidinedione plus a sulfonylurea (moderate-quality evidence) (72, 121). Although few studies reported on congestive heart failure, moderate-quality evidence from 5 observational studies favors metformin over sulfonylureas (98, 100, 125 127), and moderate-quality evidence from 4 RCTs (39, 89, 103, 105) and 4 observational studies (98, 104, 125, 127, 128) favors sulfonylureas over thiazolidinediones. One 6-month observational study reported higher rates of heart failure with the combination of a thiazolidinedione plus a sulfonylurea (0.47 per 100 person-years) than with a thiazolidinedione plus metformin (0.13 per 100 personyears) (low-quality evidence) (120). One RCT reported that the combination of a thiazolidinedione plus a sulfonylurea or metformin doubled the risk for heart failure compared with a sulfonylurea plus metformin (RR, 2.1 [CI, 1.35 to 3.27]; low-quality evidence) (129). Evidence was insufcient to show any difference among the various type 2 diabetes medications on macular edema. One RCT identied 1 person with cholecystitis out of 105 patients treated with a thiazolidinedione compared with none of 100 patients treated with metformin (lowquality evidence) (22). Another RCT identied 1 person with cholecystitis (n 280) treated with metformin monotherapy compared with no patients (n 288) treated with a combination of metformin plus a thiazolidinedione (low-quality evidence) (44). Low-quality evidence for pancreatitis came from 1 trial that reported 1 patient (n 242) with acute pancreatitis treated with a combination of metformin plus a sulfonylurea compared with no patients receiving metformin monotherapy (n 121) (49). The evidence was insufcient to show any difference in cholecystitis or pancreatitis with other monotherapies or combination therapies. For bone fractures, high-quality evidence from 1 RCT showed more bone fractures with thiazolidinedione monotherapy than with metformin monotherapy (hazard ratio [HR], 1.57 [CI, 1.13 to 2.17]), and subgroup analysis showed that the risk is higher for women (HR, 1.81 [CI, 1.17 to 2.80]; P 0.008) (130). Data were assessed from 2 RCTs and 1 observational study, and results showed fewer fractures with sulfonylureas than with thiazolidinediones (high-quality evidence) (38, 130, 131). One RCT found an increase in fractures for patients treated with rosiglitazone compared with a sulfonylurea (HR, 2.13 [CI, 1.30 to 3.51]) (130), whereas another study reported 2 ankle fractures (n 251) with pioglitazone monotherapy and no fractures with sulfonylurea monotherapy (n 251) (38). The observational study found statistically signiwww.annals.org
cantly more fractures in women treated with pioglitazone (HR, 1.70 [CI, 1.30 to 2.23]; P 0.001) and rosiglitazone (HR, 1.29 [CI, 1.04 to 1.59]; P 0.02) than with sulfonylurea (131). The combination of metformin plus a sulfonylurea was favored over the combination of thiazolidinediones plus a sulfonylurea or thiazolidinediones plus metformin (RR, 1.57 [CI, 1.26 to 1.97]; P 0.001; highquality evidence), and the RR for fractures was higher for women than men (1.82 [CI, 1.37 to 2.41] vs. 1.23 [CI, 0.85 to 1.77]) (129).
COMPARATIVE EFFECTIVENESS OF TYPE 2 DIABETES MEDICATIONS ACROSS SUBGROUPS OF ADULTS AGED 65 YEARS OR OLDER
Evidence was gathered from 28 studies (21 RCTs) that reported comparative effectiveness and safety data for subpopulations (dened by age, sex, or race; obesity, duration of diabetes, or geographic region; required medication dose; previous comorbid conditions) (5). The evidence favoring one medication over another across subgroups is not clear because of lack of sufcient power in the included studies.
SUMMARY
The evidence shows that most diabetes medications reduced HbA1c levels to a similar degree. Metformin was more effective than other medications as monotherapy as well as when used in combination therapy with another agent for reducing HbA1c levels, body weight, and plasma lipid levels (in most cases). It was difcult to draw conclusions about the comparative effectiveness of type 2 diabetes medications on all-cause and cardiovascular mortality, cardiovascular and cerebrovascular morbidity, and microvascular outcomes because of low-quality or insufcient evidence. High-quality evidence shows that the risk for hypoglycemia with sulfonylureas exceeds the risk with metformin or thiazolidinediones and that the combination of metformin plus sulfonylureas is associated with 6 times more risk for hypoglycemia than the combination of metformin plus thiazolidinediones. Moderate-quality evidence shows that the risk for hypoglycemia with metformin and thiazolidinediones is similar. Metformin is associated with an increased risk for gastrointestinal side effects. Thiazolidinediones are associated with an increased risk for heart failure, and both rosiglitazone and pioglitazone are contraindicated in patients with serious heart failure (132, 133). The current evidence was not sufcient to show any difference in effectiveness among various medications across subgroups of adults.
RECOMMENDATIONS
Recommendation 1: ACP recommends that clinicians add oral pharmacologic therapy in patients diagnosed with
Clinical Guideline
Figure 1. The American College of Physicians guideline on oral medications for type 2 diabetes.
The American College of Physicians Guideline on Oral Medications for Type 2 Diabetes
Disease or condition Target audience Target patient population Interventions Outcomes Type 2 diabetes Internists, family physicians, other clinicians Adults with type 2 diabetes Oral pharmacologic treatment for hyperglycemia in type 2 diabetes All-cause mortality Cardiovascular morbidity and mortality Cerebrovascular morbidity Neuropathy, nephropathy, retinopathy Hemoglobin A1c levels Weight Plasma lipid levels Adverse effects
Recommendations
Recommendation 1: ACP recommends that clinicians add oral pharmacologic therapy in patients diagnosed with type 2 diabetes when lifestyle modifications, including diet, exercise, and weight loss, have failed to adequately improve hyperglycemia (Grade: strong recommendation; high-quality evidence). Recommendation 2: ACP recommends that clinicians prescribe monotherapy with metformin for initial pharmacologic therapy to treat most patients with type 2 diabetes (Grade: strong recommendation; high-quality evidence). Recommendation 3: ACP recommends that clinicians add a second agent to metformin to treat patients with persistent hyperglycemia when lifestyle modifications and monotherapy with metformin fail to control hyperglycemia (Grade: strong recommendation; high-quality evidence).
Clinical Considerations
Good management of type 2 diabetes with pharmacologic and nonpharmacologic therapies is important and includes patient education, evaluation, and self-management, for microvascular and macrovascular complications, treatment of hyperglycemia, and minimization of cardiovascular and other long-term risk factors. Nonpharmacologic therapy includes dietary modifications, regular exercise, lifestyle modifications, and weight loss. Initiation of pharmacologic therapy is an important approach for the effective management of type 2 diabetes when weight loss and/or lifestyle modification fails. Metformin monotherapy was more effective in decreasing glycemic levels than other monotherapies, as well as in combination therapy with a second agent. In addition, metformin has the advantage of reducing body weight and improving plasma lipid profiles (in most cases). Although combination therapy more effectively reduces hemoglobin A1c levels, it is also associated with more adverse events.
type 2 diabetes when lifestyle modications, including diet, exercise, and weight loss, have failed to adequately improve hyperglycemia (Grade: strong recommendation; high-quality evidence). Initiation of oral pharmacologic therapy is an important approach to effective management of type 2 diabetes. There are no data on the best time to add oral therapies to lifestyle modications; thus, to avoid an unacceptable burden on patients, other complicating factors should be considered, such as life expectancy of the patient, presence or absence of microvascular and macrovascular complications, risk for adverse events related to glucose control, and patient preferences (134). The goal for HbA1c should be based on individualized assessment of risk for complications from diabetes, comorbidity, life expectancy, and patient preferences. An HbA1c level less than 7% based on individualized assessment is a reasonable goal for many but not all patients.
Recommendation 2: ACP recommends that clinicians prescribe monotherapy with metformin for initial pharmacologic therapy to treat most patients with type 2 diabetes (Grade: strong recommendation; high-quality evidence). The effectiveness, adverse effect proles, and costs of various oral pharmacologic treatments vary. Metformin is more effective than other pharmacologic agents in reducing glycemic levels and is not associated with weight gain. In addition, metformin aids in decreasing weight and reduces LDL cholesterol and triglyceride levels. Metformin was also associated with slightly lower all-cause mortality and cardiovascular mortality compared with sulfonylureas. Finally, metformin is associated with fewer hypoglycemic episodes and is cheaper than most other pharmacologic agents. Therefore, unless contraindicated, metformin is the drug of choice for patients with type 2 diabetes, in addition to lifestyle modication. Metformin is contrainwww.annals.org
Clinical Guideline
Figure 2. The American College of Physicians best practice advice: oral medications for type 2 diabetes.
The American College of Physicians Best Practice Advice: Oral Medications for Type 2 Diabetes
Disease or condition Target audience Target patient population Interventions Evidence on comparative effectiveness of oral pharmacologic agents
High-value, costconscious care
dicated in patients with impaired kidney function, decreased tissue perfusion or hemodynamic instability, liver disease, alcohol abuse, heart failure, and any condition that might lead to lactic acidosis. Physicians and patients should discuss adverse event proles before selecting a medication. Compared with baseline values, most diabetes medications (metformin, thiazolidinediones, and sulfonylureas) reduced baseline HbA1c by about 1 percentage point 3 or more months after the initiation of treatment. For adverse effects, metformin is associated with an increased risk for gastrointestinal side effects, sulfonylureas and meglitinides are associated with an increased risk for hypoglycemia, and thiazolidinediones are associated with an increased risk for heart failure (with no conclusive evidence for an increase in ischemic cardiovascular risk). However, in comparing the effectiveness of various agents, the evidence shows that metformin is the most efcacious agent as monotherapy and in combination therapy. Recommendation 3: ACP recommends that clinicians add a second agent to metformin to treat patients with persistent hyperglycemia when lifestyle modications and monotherapy with metformin fail to control hyperglycemia (Grade: strong recommendation; high-quality evidence). All dual-therapy regimens were more efcacious than monotherapies in reducing the HbA1c level in patients with type 2 diabetes by about 1 additional percentage point. Combination therapies with more than 2 agents were not included in the evidence review. No good eviwww.annals.org
dence supports one combination therapy over another, even though some evidence shows that the combination of metformin with another agent generally tends to have better efcacy than any other monotherapy or combination therapy. However, combination therapies are also associated with an increased risk for adverse effects compared with monotherapy. Generic sulfonylureas are the cheapest second-line therapy; however, adverse effects are generally worse with combination therapies that include a sulfonylurea. Although this guideline addresses only oral pharmacological therapy, patients with persistent hyperglycemia despite oral agents and lifestyle interventions may need insulin therapy. See Figure 1 for a summary of the recommendations and clinical considerations.
ACP BEST PRACTICE ADVICE

On the basis of the evidence reviewed in this paper, ACP has found strong evidence that in most patients with type 2 diabetes in whom lifestyle modications have failed to adequately improve hyperglycemia, oral pharmacologic therapy with metformin (unless contraindicated) is an effective management strategy. It is cheaper than most other pharmacologic agents, has better effectiveness, and is associated with fewer adverse effects; of note, it does not result in weight gain (Figure 2).
Clinical Guideline

10. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-60. [PMID: 12958120] 11. Qaseem A, Snow V, Owens DK, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. The development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann Intern Med. 2010;153:194-9. [PMID: 20679562] 12. Aschner P, Katzeff HL, Guo H, Sunga S, Williams-Herman D, Kaufman KD, et al; Sitagliptin Study 049 Group. Efcacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:252-61. [PMID: 20070351] 13. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979-87. [PMID: 17485570] 14. Jadzinsky M, Pfu tzner A, Paz-Pacheco E, Xu Z, Allen E, Chen R; CV181039 Investigators. Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab. 2009;11:611-22. [PMID: 19515181] 15. Williams-Herman D, Johnson J, Teng R, Luo E, Davies MJ, Kaufman KD, et al. Efcacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study. Curr Med Res Opin. 2009;25:569-83. [PMID: 19232032] 16. Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al; 1860-LIRA-DPP-4 Study Group. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet. 2010;375:144756. [PMID: 20417856] 17. Comaschi M, Demicheli A, Di Pietro C, Bellatreccia A, Mariz S; COM06 Study Investigators. Effects of pioglitazone in combination with metformin or a sulfonylurea compared to a xed-dose combination of metformin and glibenclamide in patients with type 2 diabetes. Diabetes Technol Ther. 2007;9:387-98. [PMID: 17705695] 18. Gupta AK, Smith SR, Greenway FL, Bray GA. Pioglitazone treatment in type 2 diabetes mellitus when combined with portion control diet modies the metabolic syndrome. Diabetes Obes Metab. 2009;11:330-7. [PMID: 19267711] 19. Ha llsten K, Virtanen KA, Lo nnqvist F, Sipila H, Oksanen A, Viljanen T, et al. Rosiglitazone but not metformin enhances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes. Diabetes. 2002;51:3479-85. [PMID: 12453903] 20. Iliadis F, Kadoglou NP, Hatzitolios A, Karamouzis M, Alevizos M, Karamitsos D. Metabolic effects of rosiglitazone and metformin in Greek patients with recently diagnosed type 2 diabetes. In Vivo. 2007;21:1107-14. [PMID: 18210765] 21. Natali A, Baldeweg S, Toschi E, Capaldo B, Barbaro D, Gastaldelli A, et al. Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes. Diabetes Care. 2004;27:1349-57. [PMID: 15161787] 22. Pavo I, Jermendy G, Varkonyi TT, Kerenyi Z, Gyimesi A, Shoustov S, et al. Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:1637-45. [PMID: 12679450] 23. Ramachandran A, Snehalatha C, Salini J, Vijay V. Use of glimepiride and insulin sensitizers in the treatment of type 2 diabetesa study in Indians. J Assoc Physicians India. 2004;52:459-63. [PMID: 15645955] 24. Rosenstock J, Rood J, Cobitz A, Biswas N, Chou H, Garber A. Initial treatment with rosiglitazone/metformin xed-dose combination therapy compared with monotherapy with either rosiglitazone or metformin in patients with uncontrolled type 2 diabetes. Diabetes Obes Metab. 2006;8:650-60. [PMID: 17026489] 25. Schernthaner G, Matthews DR, Charbonnel B, Hanefeld M, Brunetti P; Quartet Study Group. Efcacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. J Clin Endocrinol Metab. 2004;89:6068-76. [PMID: 15579760] 26. Amador-Licona N, Gu zar-Mendoza J, Vargas E, Sa nchez-Camargo G, Zamora-Mata L. The short-term effect of a switch from glibenclamide to metformin on blood pressure and microalbuminuria in patients with type 2 diabetes mellitus. Arch Med Res. 2000;31:571-5. [PMID: 11257323] 27. Blonde L, Rosenstock J, Mooradian AD, Piper BA, Henry D. Glyburide/
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From the American College of Physicians, Philadelphia, Pennsylvania; Oregon Health & Science University, Portland, Oregon; University of Kansas School of Medicine, Wichita, Kansas; and West Los Angeles Veterans Affairs Medical Center, Los Angeles, California.
Note: Clinical practice guidelines are guides only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians judgment. All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued. Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an ofcial position of the U.S. Department of Veterans Affairs. Financial Support: Financial support for the development of this guide-
line comes exclusively from the ACP operating budget.

Potential Conflicts of Interest: Any nancial and nonnancial conicts
of interest of the group members were declared, discussed, and resolved. A record of conicts of interest is kept for each Clinical Guidelines Committee meeting and conference call and can be viewed at www .acponline.org/clinical_information/guidelines/guidelines/conicts_cgc .htm. Disclosures can be viewed at www.acponline.org/authors/icmje /ConictOfInterestForms.do?msNumM11-2857.
Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, Amer-
ican College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106; e-mail, aqaseem@acponline.org. Current author addresses and author contributions are available at www .annals.org.
References
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Clinical Guideline
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Current Author Addresses: Drs. Qaseem and Starkey: 190 N. Indepen-
dence Mall West, Philadelphia, PA 19106. Dr. Humphrey: 3710 SW U.S. Veterans Hospital Road, Portland, OR 97207. Dr. Sweet: 1010 North Kansas, Wichita, KS 67214. Dr. Shekelle: 11301 Wilshire Boulevard, Los Angeles, CA 90073.
Author Contributions: Conception and design: A. Qaseem, P. Shekelle. Analysis and interpretation of the data: A. Qaseem, L.L. Humphrey. Drafting of the article: A. Qaseem, M. Starkey. Critical revision of the article for important intellectual content: A. Qaseem, L.L. Humphrey, P. Shekelle. Final approval of the article: A. Qaseem, L.L. Humphrey, P. Shekelle. Statistical expertise: A. Qaseem. Administrative, technical, or logistic support: A. Qaseem, M. Starkey. Collection and assembly of data: A. Qaseem, M. Starkey.
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7 February 2012 Annals of Internal Medicine Volume 156 Number 3 W-41
Appendix Table 1. Type 2 Diabetes Medications, Dosages, and Wholesale Price Range*
Drug Type and Dosage Price for 1-Month Supply Generic Metformin 500 mg once daily 500 mg twice daily 500 mg 3 times daily 850 mg once daily 850 mg twice daily 850 mg 3 times daily 1000 mg once daily 1000 mg twice daily Metformin (extended release) 500 mg once daily 1000 mg once daily 1500 mg once daily 2000 mg once daily Second-generation sulfonylureas Glimepiride 1 mg once daily 2 mg once daily 4 mg once daily 8 mg once daily Glipizide 5 mg once daily 10 mg once daily 10 mg twice daily 20 mg twice daily Glipizide (extended release) 5 mg once daily 20 mg once daily Glyburide 2.5 mg twice daily 5 mg once daily 5 mg twice daily Micronized glyburide 1.5 mg once daily 3 mg once daily 6 mg twice daily Meglitinides Repaglinide 0.5 mg 3 times daily 1 mg 3 times daily 4 mg 3 times daily Nateglinide 60 mg 3 times daily 120 mg 3 times daily Thiazolidinedione Pioglitazone 15 mg once daily 30 mg once daily 45 mg once daily DPP-4 inhibitors Sitagliptin 100 mg once daily Saxagliptin 2.55 mg once daily $ $$ $$ $$ $$$ $$$ $$ $$$ Brand $$ $$ $$$ $$ $$$ $$$$ $$ $$$$
Appendix Table 1Continued

Drug Type and Dosage Price for 1-Month Supply Generic GLP-1 agonists Exenatide Injection of Injection of Liraglutide Injection of Injection of Injection of Brand
5 mcg twice daily 10 mcg twice daily 0.6 mcg twice daily 1.2 mcg twice daily 1.8 mcg twice daily
NA NA NA NA NA
$$$$$ $$$$$ $$$$ $$$$$ $$$$$
$ $$ $$ $$$
$$ $$ $$$ $$$$
DPP-4 dipeptidyl peptidase-4; GLP-1 glucagon-like peptide-1; NA not available. * Adapted from the Agency for Healthcare Research and Quality Clinician Research Summary. $ $5 to $25; $$ $26 to $75; $$$ $76 to $125; $$$$ $126 to $200; $$$$$ $200.
$ $ $$ $$$ $ $$ $$$ $$ $ $$ $$ $$ $$ $ $ $$
$ $$ $$ $$$ $$ $$ $$$$ $$$ $ $$$ $$ $$ $$$ $$ $$ $$$$
NA NA NA NA NA
$$$$$ $$$$$ $$$$$ $$$$ $$$$
NA NA NA
$$$$ $$$$$ $$$$$
NA NA
$$$$$ $$$$$
W-42 7 February 2012 Annals of Internal Medicine Volume 156 Number 3
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Appendix Table 2. Key Findings and Strength of Evidence for Long-Term Outcomes
Comparison All-Cause Mortality Cardiovascular Mortality Cardiovascular and Cerebrovascular Morbidity Nephropathy and Neuropathy
Monotherapy vs. monotherapy Metformin vs. TZD Sulfonylurea DPP-4 inhibitor Meglitinide GLP-1 agonist TZD vs. TZD Sulfonylurea DPP-4 inhibitor Meglitinide GLP-1 agonist Sulfonylurea vs. DPP-4 inhibitor Meglitinide GLP-1 agonist DPP-4 inhibitor vs. Meglitinide GLP-1 agonist Monotherapy vs. combination therapy Metformin vs. Metformin TZD Metformin sulfonylurea Metformin DPP-4 inhibitor Metformin meglitinide
Neither favored, low Favors metformin, low Unclear, low Unclear, low Insufficient Insufficient Neither favored, low Insufficient Insufficient Unclear, low Insufficient Unclear, low Insufficient Insufficient Insufficient
Neither favored, low Favors metformin, low Insufficient Unclear, low Insufficient Insufficient Unclear, low Insufficient Insufficient Insufficient Insufficient Unclear, low Insufficient Insufficient Insufficient
Unclear, low Unclear, low Insufficient Unclear, low Insufficient Unclear, low Unclear, low Insufficient Insufficient Unclear, low Insufficient Unclear, low Insufficient Insufficient Insufficient
Favors pioglitazone*, moderate Unclear, low* Insufficient Insufficient Insufficient Insufficient Insufficient Unclear, low* Insufficient Unclear, low* Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient
Unclear, low Neither favored, low Unclear, low Unclear, low
Unclear, low Unclear, low Unclear, low Unclear, low
Unclear, low Favors Met, low Unclear, low Unclear, low
Insufficient* Unclear, low Insufficient Insufficient* unclear, low Insufficient
Combination therapy vs. combination therapy Metformin another agent vs. Metformin TZD Unclear, low Metformin sulfonylurea Metformin meglitinide Metformin DPP-4 inhibitor Metformin GLP-1 agonist Metformin basal insulin Metformin premixed insulin TZD another agent vs. Metformin TZD Metformin sulfonylurea Metformin meglitinide Metformin DPP-4 inhibitor Metformin GLP-1 agonist Metformin basal insulin Metformin premixed insulin Unclear, low Unclear, low Unclear, low Insufficient Insufficient Unclear, low Insufficient Unclear, low Unclear, low Insufficient Insufficient Unclear, low Unclear, low
Unclear, low Unclear, low Insufficient Unclear, low Unclear, low Unclear, low Unclear, low Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient
Unclear, low Unclear, low Insufficient Unclear, low Insufficient Unclear, low Insufficient Unclear, low Unclear, low Insufficient Insufficient Insufficient Insufficient Unclear, low
Conclusion unclear for nephropathy and neuropathy, low Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient
DPP-4 inhibitor dipeptidyl peptidase-4; GLP-1 glucagon-like peptide-1; TZD thiazolidinedione. * Key nding for nephropathy. Key nding for neuropathy.
www.annals.org
Appendix Table 3. Key Findings and Strength of Evidence for Adverse Events*
Liver Injury GI Event CHF Macular Edema Pancreatitis or Cholecystis Fractures
Comparison
Hypoglycemia
Monotherapy vs. monotherapy Metformin vs. TZD Neither favored, moderate Unclear, low Insufficient Insufficient Insufficient Unclear, low Neither favored, high Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Favors sulfonylurea, low Insufficient Insufficient Insufficient Insufficient Insufficient Unclear, low Insufficient Insufficient Insufficient Insufficient Neither favored, high Favors sulfonylurea, moderate Insufficient Insufficient Unclear, low Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Favors sulfonylurea, moderate Insufficient Favors TZD, high Neither favored, moderate Insufficient
Neither favored, moderate
Favors metformin, high Unclear, low Insufficient Insufficient Insufficient Insufficient Favors sulfonylurea, high

Favors metformin, low Insufficient Insufficient Favors metformin, moderate Insufficient Favors DPP-4 inhibitor, moderate Favors meglitinides, low Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Neither favored, low Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Neither favored, low Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Favors metformin TZD, moderate Favors metformin sulfonylurea, moderate Unclear, low Unclear, low Favors metformin, low Unclear, low Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Favors metformin TZD, low Insufficient Favors metformin, low Insufficient Insufficient Unclear, low Insufficient
Sulfonylurea
DPP-4 inhibitor
Neither favored, high
Meglitinide
GLP-1 agonist TZD vs. TZD
Favors metformin, moderate Insufficient
W-44 7 February 2012 Annals of Internal Medicine Volume 156 Number 3
Sulfonylurea
Favors rosiglitazone, low Favors TZD, high
DPP-4 inhibitor Meglitinide GLP-1 agonist Sulfonylurea vs. DPP-4 inhibitor
Insufficient Favors TZD, low Insufficient
Meglitinide GLP-1 agonist
Favors DPP-4 inhibitor, moderate Favors meglitinides, low Favors GLP-1 agonist, high
DPP-4 inhibitor vs. Meglitinide GLP-1 agonist
Monotherapy vs. combination therapy Metformin vs. Metformin TZD Favors metformin, moderate Metformin Favors metformin, sulfonylurea moderate
Metformin DPP-4 inhibitor Metformin meglitinide
Neither favored, moderate Favors metformin, low
www.annals.org
Continued on following page
www.annals.org Liver Injury GI Event CHF Macular Edema Pancreatitis or Cholecystis Fractures Neither favored, low Insufficient Unclear, low Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Unclear, low Unclear, low Favors metformin sulfonylurea, low Neither favored, low Neither favored, low Insufficient Favors metformin other, low Insufficient Insufficient Favors metformin other, high Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Neither favored, low Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Favors TZD other, moderate Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Favors metformin TZD, low Favors metformin sulfonylurea, low Insufficient Insufficient Favors metformin sulfonylurea, high Insufficient Insufficient Insufficient Insufficient Insufficient
Appendix Table 3Continued
Comparison
Hypoglycemia
Combination therapy vs. combination therapy Metformin another agent vs. Metformin TZD Favors metformin TZD, high Metformin Unclear, low sulfonylurea Metformin Insufficient meglitinide Metformin DPP-4 Insufficient inhibitor Metformin GLP-1 Insufficient agonist Metformin basal Favors metformin insulin basal insulin, moderate Metformin premixed Insufficient insulin TZD another agent vs. Metformin TZD Favors metformin TZD, low Metformin Favors TZD sulfonylurea sulfonylurea, low Metformin Insufficient meglitinide Metformin DPP-4 Insufficient inhibitor Metformin GLP-1 Insufficient agonist Metformin basal Insufficient insulin Metformin premixed Insufficient insulin
CHF congestive heart failure; DPP-4 inhibitor dipeptidyl peptidase-4; GI gastrointestinal; GLP-1 glucagon-like peptide-1; TZD thiazolidinedione. * Unless otherwise noted, comparisons and intermediate outcomes were graded as insufcient because there were no studies. Key nding and evidence grade for cholecystitis. Key nding and evidence grade for pancreatitis. For diarrhea only. With lower dose of metformin. For dyspepsia.
CORRECTION: ORAL PHARMACOLOGIC TREATMENT TYPE 2 DIABETES MELLITUS
OF
The rst full sentence on page 224 of a recent guideline (1) should read as follows: Metformin was also favored over sulfonylureas for cardiovascular mortality (low-quality evidence), as evidenced by 4 cohort studies (92, 94, 96, 101), although 1 prospective cohort study (94) showed slightly higher cardiovascular mortality rates for metformin than for sulfonylurea monotherapy. Also, ADOPT (A Diabetes Outcome Progression Trial) (89) reported only
1 fatal CHF event in patients treated with either metformin or glyburide (nonstatistically signicant difference), but patients treated with glyburide generally experienced fewer CHF as well as cardiovascular events.
Reference
1. Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P, for the Clinical Guidelines Committee of the American College of Physicians. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2012;156:218-231.

ACP 2012 - Oral Pharmacologic Treatment of Type 2 DM

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Clinical Guideline

Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus

Table 1. The American College of Physicians Guideline

Weak Weak Weak

Insufficient evidence to determine net benefits or risks

COMPARATIVE EFFECTIVENESS OF TYPE 2 DIABETES MEDICATIONS ON INTERMEDIATE OUTCOMES

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Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus

Table 2. Key Findings and Strength of Evidence for Intermediate Outcomes*

Neither favored, moderate

Favors metformin, high

Neither favored, moderate Favors pioglitazone, high

Sulfonylurea DPP-4 inhibitor Meglitinide

GLP-1 agonist TZD vs. TZD Sulfonylurea

Favors metformin, high Favors metformin, moderate Unclear, low

Neither favored, high Neither favored, low Unclear, low

Insufficient Favors pioglitazone, low Favors sulfonylurea, low

DPP-4 inhibitor Meglitinide

Insufficient Unclear, low

GLP-1 agonist Sulfonylurea vs. DPP-4 inhibitor Meglitinide

Insufficient Unclear, low Neither favored, high

Insufficient Neither favored, low Neither favored, low

GLP-1 agonist DPP-4 inhibitor vs. Meglitinide GLP-1 agonist

Favors GLP-1 agonist, moderate Insufficient Insufficient

Unclear, low Insufficient

Favors metformin, high

Favors metformin, high Unclear, low

Metformin sulfonylurea Metformin DPP-4 inhibitor Metformin meglitinide

Favors metformin, high Neither favored, moderate Favors metformin, low

Neither favored, low Neither favored, low

Neither favored, low

Favors metformin sulfonylurea, moderate

Metformin meglitinide Metformin DPP-4 inhibitor

Neither favored, low Insufficient Neither favored, low

Favors metformin DPP-4 inhibitor, low

Continued on following page

220 7 February 2012 Annals of Internal Medicine Volume 156 Number 3

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Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus

Favors TZD sulfonylurea, low

Insufficient Neither favored, low

Insufficient Unclear, low Neither favored, low

Unclear, low Insufficient

Neither favored, low Insufficient

Favors metformin sulfonylurea, low

Unclear, low Favors metformin sulfonylurea, low Insufficient

Unclear, low Favors pioglitazone sulfonylurea, low Insufficient

Unclear, low Favors pioglitazone sulfonylurea, low Insufficient

Neither favored, low Neither favored, low

Favors metformin GLP-1 agonist, low

Favors metformin GLP-1 agonist, low

Neither favored, low

Monotherapy vs. Monotherapy

Combination Therapy vs. Combination Therapy

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Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus

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Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus

COMPARATIVE EFFECTIVENESS OF TYPE 2 DIABETES MEDICATIONS ON LONG-TERM CLINICAL OUTCOMES

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Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus

COMPARATIVE SAFETY MEDICATIONS

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